While tailored smoking cessation interventions have generally demonstrated positive outcomes, the mechanisms by which people respond to these interventions are less well understood. We are proposing a series of studies that examines the neural substrates associated with smoking cessation messages individually tailored to smokers'needs and interests. The proposed project uniquely combines cognitive neuroscience and public health communications methods to investigate how smokers respond to tailored smoking cessation messages. We have demonstrated in a preliminary functional magnetic resonance imaging (fMRI) study that smokers receiving high-tailored smoking cessation messages (compared to low-tailored cessation messages) showed greater medial prefrontal cortex (MPFC) activation, consistent with the role of MPFC in processing self-relevant material. To further investigate the neural substrates that respond to specific tailored smoking cessation messages and importantly the relationship of these findings to subsequent actual smoking cessation, we propose two studies, each with two phases. Study 1a (Phase I) investigates the role of self-relevance in targeted messaging for smoking cessation. We will examine the relative activation of the MPFC in each subject during exposure to highly self-relevant, high-tailored smoking cessation messages in contrast to low-tailored self-relevant messages and a control self-relevance task. 88 cigarette smokers will receive high-tailored and low-tailored self-relevant smoking cessation messages during fMRI, and will also complete a control task testing self-relevance (Phan et al., 2004). The findings will inform whether greater MPFC activation to high- tailored self-relevant smoking cessation messages is associated with greater self-referential processing. In Study 1b (Phase 2), we will administer to each Study 1a participant a previously tested web-based tailored smoking cessation program immediately following the fMRI scanning (Study 1a) session. Subjects will be followed up in four months and assessed on actual smoking abstinence. Study 1b will explore associations between specific brain region activations from self-relevant smoking messages and subsequent cessation. Study 2 investigates the role of two different types of smoking cessation messages: motivational messages (why to quit) and instructional messages (how to quit) in targeted messaging for smoking cessation. In Study 2a (Phase1), another 88 cigarette smokers will receive high-tailored motivational messages, high-tailored instructional messages, and neutral messages during fMRI. In Study 2b (Phase 2), Study 2a participants will receive the web-based tailored smoking cessation program immediately after the fMRI scanning session and then be followed up in four months to determine actual smoking abstinence. Study 2b will explore the relationship between specific brain region activations in response to tailored motivational and instructional cessation messages and subsequent cessation. The results of these studies will begin to identify specific pathways for optimal message tailoring to make the largest impact on smoking cessation. Nicotine addiction is an important public health concern. The project combines public health, psychology, and neuroscience research methods to understand how smokers respond to individualized smoking cessation messages in an effort to improve smoking cessation programs.